Atherosclerosis is a chronic inflammatory disease that arises due to a combination of various stimuli, such as cytokines and disturbed blood flow. These stimuli result in pro-inflammatory cell adhesion molecule expression, an early event in atherogenesis, which recruit leukocytes to the activated endothelium, leading to a chronic inflammatory state. Although the use of preventative pharmacological approaches for these conventional risks, such as lipid lowering and antihypertensive drugs, have been beneficial, there is no treatment available to reduce these early steps of atherogenesis. Focal adhesion kinase (FAK) is an integrin-associated protein tyrosine kinase that plays a critical role in maintaining normal vascular physiology upon changes in both cytokine and blood flow signaling. Our preliminary findings have revealed that FAK inhibition in endothelial cells (EC) prevented tumor necrosis factor-? (TNF-?)-induced expression of various pro-inflammatory molecules, suggesting a potential ?ant-inflammatory role? for FAK inhibition. Interestingly, in ApoE-/- model, FAK inhibitor was able to block vascular cell adhesion molecule-1 (VCAM-1) expression and reduced macrophage recruitment, implicating FAK as a potential target for atherosclerosis. While NF-?B is normally inhibited by I?B?, inflammatory stimuli lead to rapid I?B? degradation and NF-?B activation. I?B? is then upregulated by NF-?B activity, thus inhibiting NF-?B. In atherosclerosis, however, sustained NF-?B activation occurs due to continued inflammatory stimuli, which leads to oscillations of NF-?B activity as I?B? is continually made and degraded. We discovered that FAK inhibition in ECs prevented sustained NF-?B activation due to increased stability of I?B?, sequestering NF-?B in cytoplasm inactive. Further, we found that this long term I?B? stabilization by FAK inhibition may be mediated by reduced FAK-mediated tyrosine phosphorylation of I?B? kinase (IKK). Taken together, our data suggest that FAK activity drives TNF-?-induced pro-inflammatory gene expression through sustained NF-?B oscillations. Surprisingly, FAK inhibitor blocks plaque formation in ApoE -/- model of disturbed flow, indicating a potential role of FAK activity in flow signaling. Taken together, our central hypothesis is that FAK inhibition may prevent atherosclerosis by blocking stimuli-induced pro-inflammatory molecule expression via dampened NF-?B oscillations. In aim-1, we will determine the molecular mechanism of FAK action in maintaining sustained NF-?B signaling upon TNF-? and disturbed blood flow in ECs. In aim-2, we will evaluate if FAK-mediated NF-?B activity in ECs has therapeutic potential by using pharmacological and genetic FAK atherosclerosis mouse models. This study will produce new insights into atherogenesis via FAK-mediated NF-?B activity in ECs. Furthermore, FAK inhibitor's ability to block sustained NF-?B activity and plaque formation might provide a new therapeutic option in the treatment vascular inflammatory diseases.